The autosomal recessive syndrome ataxia-telangiectasia (A-T) is of public health importance because there is evidence that A-T heterozygotes, estimated to comprise 1.4% of the United States white population, are predisposed to cancer, particularly female breast cancer with onset before age 65. The initial mapping of the principal, perhaps only, A-T gene to 11q22-23 provides the basis for full characterization of this gene at the DNA and protein level, detection of A-T heterozygotes in A-T families and the general population, strong confirmation of the association of A-T heterozygosity with specific cancers, understanding of the gene-environment interactions that produce these cancers, and, in the long term, prevention of these cancers in all A-T heterozygotes in the general population. Fine mapping with available and to-be-developed highly polymorphic DNA probes will be done to localize the A-T locus at 11q22-23 and to resolve the question of non-allelic heterogeneity. Assay systems will be developed to test candidate regions for the A-T locus and available cosmid clones will be tested to see if they transform A-T homozygous cells to the heterozygous phenotype. Ultimately, the specific region that appears to contain the A-T allele will be confirmed in these systems, and the A-T allele characterized. A case-control analysis based on direct identification of A-T heterozygotes will test the hypothesis that A-T heterozygotes are predisposed to breast and other cancers. Allele-specific or closely linked DNA probes will be used to determine which blood relatives with cancer are A-T heterozygotes, so that a newly developed, well controlled, statistically powerful method can be used to provide strong independent evidence about specific cancers associated with A-T heterozygosity. Breast cancer is the highest priority.